Spread & Containment
PASTE, Don’t Cut: Genome Editing Tool Looks Beyond CRISPR and Prime
A recently patented genome editing tool called PASTE holds genuine promise for expanding the universe of treatable genetic diseases.
The post PASTE, Don’t…
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A recently patented genome editing tool called PASTE holds genuine promise for expanding the universe of treatable genetic diseases. The approach combines elements of CRISPR and prime editing with a pair of enzymes designed to enable the integration of large segments of DNA without incurring double-stranded DNA breaks.
U.S. Patent No. 11,572,556, assigned to MIT, covers systems, methods, and compositions for programmable addition via site-specific targeting elements (PASTE). The patent describes site-specific integration of a nucleic acid into a genome, using a CRISPR–Cas9 nickase fused to a reverse transcriptase (RT) and a serine integrase. These enzymes target specific genome sequences known as attachment sites, binding to them before integrating their DNA payload.
PASTE can insert DNA fragments as large as 50,000 base pairs, which puts it on a different plane compared to other genome editing tools such as prime editing.
The credited inventors are Omar Abudayyeh, PhD, and Jonathan Gootenberg, PhD, two McGovern fellows at MIT’s McGovern Institute for Brain Research. The duo, who were both graduate students with CRISPR pioneer Feng Zhang, PhD, at the Broad Institute before moving across the road to the McGovern Institute in Kendall Square, Cambridge, MA, first detailed PASTE in a preprint posted on bioRxiv in 2021. The peer-reviewed paper, “Drag-and-drop genome insertion of large sequences without double-strand DNA cleavage using CRISPR-directed integrases,” was published in November 2022 in Nature Biotechnology.
PASTE entails the engineering of Cas9, RT, and integrase linkers to create a fusion protein capable of efficient integration (5–50%) of diverse cargos at precisely defined target locations within the human genome with small, stereotyped scars that can serve as protein linkers.
The serine integrases used in PASTE can insert DNA sequences as large as 50,000 base pairs by targeting specific “attachment” sites within the genome.
“It has been very difficult for the [CRISPR] field to really put large edits in the genome without relying on things like homology-directed repair,” Gootenberg told GEN Edge. “The concept of PASTE is actually quite simple: Instead of being able to try to do everything all at once in one conceptual aspect—and there are some technologies that approach that—we thought it would be easier to take something that can insert very efficiently into a constant sequence like an integrase, and then put the constant sequence into the genome.”
“It’s a two-step process where we first insert the constant sequence, which is a small letter, and it’s easier to do. Then we use that constant sequence to put in a larger sequence. That’s the concept in a nutshell,” Gootenberg added.
The $64-million question
Jacob S. Sherkow, JD, a professor at the University of Illinois College of Law and the Carle Illinois College of Medicine, and an authority on the long-standing CRISPR-Cas9 patent standoff, told GEN Edge that PASTE appears to address a key challenge in genome editing: How to achieve high fidelity site-specific insertion of an exogenous target sequence?
Citing the three-prong standard for patentability—novelty, utility, and non-obviousness—Sherkow said MIT and the PASTE inventors can likely show their technology is novel and useful. But it is less clear if they can show non-obviousness should the PASTE patent be challenged someday.
“That is the $64-million question,” said Sherkow. “To the extent that there’s patent litigation, I assure you that on the PASTE patent, at least some of those arguments are going to turn on non-obviousness.”
“You’ve got the older Liu prime editing patent that claims prime editing. Then you’ve got [the] PASTE patent filed later, which claims 80% of what the prime editing patent claims, plus the addition of using an interface and an RT, to insert a large piece of DNA in a site-specific site. That is not an overlap issue at all, such that the patent office is going to be asked to, or have the authority to, cancel one patent in favor of the other,” Sherkow said.
“Where the conflict is going to arise is not on the validity of these two patents. It’s going to be on who is going to pay for them, and who is going to use which technology over another technology,” Sherkow added.
PASTE and prime are among numerous technologies that have developed in the emerging genome editing field as researchers and startups pursue curative therapies that make changes to the genome without making double-stranded breaks, a known downside of traditional CRISPR-Cas9 gene editing that can be harmful to cells. Last year, Intellia Therapeutics shelled out up to $200 million to buy University of California, Berkeley, startup Rewrite Therapeutics and its DNA writing technology.
Patentability is among the key challenges for genome editing. For example, Tessera Therapeutics is pursuing a patent for its RNA gene writers technology, which uses a mechanism called target primed reverse transcription to write genes into the genome. The method involves four steps—binding RNA, binding DNA, nicking DNA, and priming reverse transcription. The company is among several whose intellectual property has been challenged in a recent STAT article as “bear[ing] strong similarity to prime editing—even if they use different terminology.”
Blanket therapy
PASTE editing could potentially treat diseases caused by genes harboring a large number of mutations, such as Leber’s congenital amaurosis or cystic fibrosis, where gene editing systems would have to be tailored for specific mutations and each subset of a disease population. In those diseases, programmable insertion of a wild-type gene could address most potential mutations and serve as a blanket therapy.
“Complete replacement of genes at their natural sites can be contemplated instead of creating variant-specific treatments,” Muhammad Arslan Mahmood, MPhil, and Shahid Mansoor, PhD, both of Pakistan’s National Institute for Biotechnology and Genetic Engineering, observed in a recent commentary on the PASTE report, published in The CRISPR Journal (a sister journal of GEN).
“These exciting results enhance the versatility of the CRISPR-based gene editing along with the LSRs [large serine recombinases] that provide the opportunity for genome engineering, combinatory screening of bulky DNA libraries aiding to spread these applications for treating the diseases in both animals and plants, which are caused by defective genes,” the authors concluded.
The Cystic Fibrosis Foundation is among the entities that have funded PASTE editing research, through a Pioneer Award designed to fund “ambitious basic research projects aiming to utilize cutting-edge techniques and strategies that have the potential to discover new genetic-based therapies for cystic fibrosis.”
“We’ve been working on actually being able to insert the genes at the locus, and things are looking promising with that. We’ll have more to share about that as things progress. I would say that’s one of the main funded applications we’re looking at right now,” Gootenberg said.
Carrying out genome editing without the need for double-stranded breaks in DNA was first laid out by David Liu, PhD, and colleagues at the Broad Institute of MIT and Harvard. In a pair of papers in Nature published between 2015–16, Liu’s lab developed base editing, a technique that can make certain classes of single-base substitutions without cleaving the double helix (unlike CRISPR-), two former postdocs in Liu’s lab, Alexis Komor, PhD (now of University of California, San Diego) and Nicole Gaudelli, PhD (now of Beam Therapeutics) recalled in a 2020 episode of The CRISPR Journal’s podcast series GuidePost, available via SoundCloud and Spotify.
Later, in a 2019 paper published in Nature, Andrew Anzalone, MD, PhD, and colleagues in Liu’s lab described a “search-and-replace” genome editing technology called prime editing. That approach supplied a desired edit in an extension to the guide RNA, which is then converted to DNA using the RT enzyme. The technology can introduce targeted insertions, deletions, and all 12 possible base-to-base substitutions.
Liu told GEN at the time that of the roughly 75,000 cataloged pathogenic mutations in human genetic diseases, prime editing had the versatility and potential to correct the majority (89%) of them.
Liu’s 2019 paper showed prime editing being used to install an integrase/recombinase landing site into a target DNA site. Earlier, in March of that year, Liu and colleagues filed for a U.S. patent that was granted in September 2022 (No. 11,447,770), which described several examples using prime editing to install integrase/recombinase landing sites, followed by targeted gene integration using an integrase/recombinase enzyme.
And in a 2021 paper published in Nature Biotechnology, Liu and co-authors reported the use of prime editing to install an integrase/recombinase landing site into a target DNA site, followed by an integrase/recombinase to catalyze integration of cargo DNA into that landing site.
Prime vs. PASTE
Speaking with GEN Edge, Liu asserted that one distinction between PASTE and Prime’s PASSIGE (prime-assisted site-specific integrase gene editing) approach is that PASTE fuses the prime editor and the integrase enzyme into a single protein chain, while PASSIGE typically uses them as two separate proteins.
“We have compared, side-by-side, fused and unfused prime editors plus integrases at several different target sites in human cells, and we have never observed any benefit from fusing the prime editor and integrase,” said Liu, who is also the director of the Merkin Institute of Transformative Technologies in Healthcare and a Howard Hughes Medical Institute investigator.
“Indeed, for most of the target sites and integrase enzyme combinations we’ve tested in human cells, we observed that the fused prime editor–integrase proteins as reported in the PASTE paper substantially underperform the separated prime editor and integrase proteins as used in PASSIGE,” Liu said. “That separate prime editor + integrase proteins perform better than fusing the two proteins together makes sense scientifically, because the prime editor must vacate the target landing site before the integrase enzyme can perform cargo DNA integration.”
Liu said fusing the two proteins together increases the chance that the target landing site is blocked by the prime editing protein and/or associated prime editing guide RNA (pegRNA), “because the integrase must compete with an always-nearby prime editor to access the target landing site when the two proteins are tethered.”
“In contrast, fusing the DNA-nicking Cas protein and the engineered reverse transcriptase together into a prime editor protein makes sense because the Cas protein must hold open—or melt—the two DNA strands in order for the nicked target DNA strand to prime reverse transcription, initiating the prime editing process,” Liu added. “In this case, fusing the Cas nickase to the engineered reverse transcriptase offers a benefit because it keeps the engineered reverse transcriptase nearby, poised to act on the opened and nicked target DNA site.”
“In other words,” Liu said, “the two proteins, in this case, act together, whereas in the case of PASSIGE/PASTE the two proteins must act separately.”
Liu co-founded Prime Medicine to commercialize prime editing based on Anzalone’s groundbreaking work when he was a postdoctoral fellow in Liu’s lab. Anzalone recently discussed the technology and the company on GEN’s “Close to the Edge” video interview series. (Anzalone is Prime’s lead developer of prime editing, and the company’s scientific co-founder and head of its prime editing platform.)
Search and replace
Prime says its editors can change any nucleotide to any other base, delete DNA sequences to correct insertion mutations, or insert DNA sequences to correct deletion mutations. Prime editors can also alter the regulatory regions of genes, insert or create premature stop codons, and modify splicing sequences.
Last year, Prime completed an initial public offering (IPO) that raised about $180 million despite the bear market for newly-public biotechs. In its prospectus, Prime revealed an 18-program pipeline and the in-licensing of U.S. Patent No. 11,447,770, which covers methods of using Prime Editors, was granted on September 20, 2022, and expires in 2040.
“We are confident in the strength of our patent portfolio,” Prime Medicine said in a statement to GEN Edge. “Broad Institute’s in-licensed IP includes an issued U.S. patent broadly covering Prime Editing methods and an allowed U.S. application, which is expected to issue shortly, covering pegRNAs. Our Prime Editing patent portfolio includes numerous in-licensed and Prime Medicine-owned patent applications in the U.S. and worldwide.”
Both the Broad Institute and Prime Medicine have filed for patent protection covering technological advancements that will “greatly” expand the scope of Prime Editing.
“We have in-licensed all Prime Editing improvements from Dr. Liu’s lab and anticipate continuing to do so in the future. We believe these investments, along with our continuing relationship with Dr. Liu, establish Prime Medicine as a clear leader in Prime Editing,” the company added. “We plan to continue investing in our Prime Editing technology with a focus on reinforcing our leadership position and making fundamental progress towards better therapies for patients.”
Prime has just announced the selection of its first development candidate—PM359, a treatment for chronic granulomatous disease, after observing long-term in vivo engraftment of Prime Edited hematopoietic stem cells (HSCs) in a mouse model of the disease.
“We look forward to advancing PM359 into investigational new drug (IND)-enabling studies later this year, while continuing to advance our broader portfolio toward additional preclinical proof-of-concept readouts,” Keith Gottesdiener, MD, Prime’s president and CEO, said in a statement.
Last January, Prime announced positive preclinical data for three of its development programs—candidates to treat Friedrich’s ataxia, cystic fibrosis, and Wilson’s disease. In addition, Prime said its PASSIGE platform achieved an approximately 60% precise insertion of a 3.5-kilobase transgene of interest at a single targeted site in primary human T cells, resulting in positive expression of the gene product.
Light bulb moment
Asked about the potential for a challenge to the PASTE patent, Gootenberg said: “It’s obviously going to be a complex situation with intersecting IP, as has been with Cas9 and other nucleases from the start. But that said, we’re really excited about how we can develop these technologies and move these technologies forward to develop actual cures for patients.”
Abudayyeh and Gootenberg are veterans of genome editing, having previously discovered Cas13, an RNA-targeting nuclease in the lab of Zhang, and later through their own lab, discovered the CRISPR effector protein Cas7-11. Abudayyeh and Gootenberg set up their joint lab at the McGovern Institute in 2019, bypassing the traditional postdoc path so they could keep working together.
“We had been basically interested in targeted gene integration for a long time. When we saw the paper, a light bulb went off in our heads,” Abuddayeh recalled. “We were like, whoa, wait a second! We saw these integrases that we were familiar with already. If we could somehow combine these systems together and basically use them to lay (at) the target site too.”
“When we first started down this path, Cas9 was the only thing people were focusing on for programmable double-stranded cleavage and editing. We asked the question of whether we can go beyond Cas9,” Abuddayeh added.
Gootenberg and Abudayyeh have licensed the technology behind PASTE editing to a startup they co-founded, Tome Biosciences, which has reportedly raised more than $95 million from several big-name investors, including Andreessen Horowitz (a16z), ARCH Venture Partners, and Polaris Partners. Other reported investors include Alexandria Venture Investments, Google’s GV, and Longwood Fund.
“Were it not for the weak market, I suspect (the PASTE patent) would have propelled CRISPR-related stocks higher. But this also demonstrates that—while markets are weak—innovation in the space is still going strong,” Jeff Brown, founder and chief investment analyst for Brownstone Research wrote last September on the investment firm’s website. “It’s advancements like this that will propel the entire industry forward—and move stock prices—when healthier markets return.”
Abudayyeh and Gootenberg would not discuss Tome Biosciences, which has said little about its operations publicly. Its website simply consists of a home page and a listing of more than a dozen available jobs. Tome was among companies that presented last year at GEN’s virtual presentation, “The State of Biotech”
On a roll
Tome is one of several companies co-founded by Gootenberg and Abudayyeh; the duo also co-founded Sherlock Biosciences, which recently gained rights to a U.S. patent for diagnostic use of a CRISPR system based on Cas12; Proof Diagnostics, a CRISPR-based COVID-19 molecular test developer; and Moment Biosciences, which has described itself as a precision microbiome therapy developer.
In the PASTE study published last year, Abuddayeh, Gootenberg, and a team of more than two dozen co-authors detailed how they delivered genes ranging from 779 to 36,000 base pairs—a range that would enable insertion of >99.7% of human cDNAs as transgenes—to three human cell lines, primary human T cells, and liver cells, as well as to liver cells in mice. The researchers were able to insert genes in mice with success rates that ranged from 5–60%, with “minimal” formation of indels at the integration sites.
The researchers tested the delivery system with 13 payload genes, including some that could be therapeutically useful, and were able to insert them into nine different locations in the genome.
Can PASTE transport genes larger than 36,000 base pairs?
“We’ve not done larger, but there’s no reason I think why you couldn’t do larger,” Abudayyeh said. “It becomes a delivery problem: How do we get 50,000 base pair templates into a human cell? The reason we’re able to max out at approximately 36 kb is because we’re using an adenoviral construct. Adenoviruses are approximately a 36-kb genome, so it’s easy to get that into the cell.”
Abudayyeh said they’ve been approached by scientists interested in inserts of 50–100 kb. “We just haven’t gone down that path,” he said. On its website, Tome Biosciences suggests it can handle DNA segments of that size range: “Using CRISPR, our technologies allow us to insert any genetic sequence of any size at any location into any genome.”
Beyond patent validity
While users of prime editing do not likely need a license covering PASTE, Sherkow added: “By contrast, if you are using the PASTE technology, there is, I think, an outstanding question as to whether you will also need to obtain a prime patent license.”
How companies answer that question will depend, he said, on how they use both PASTE and prime technology. “This is more just, frankly, garden-variety technology, improvement licensing stuff that happens in a variety of other fields,” Sherkow said. “It is not this cataclysmic dispute with respect to who got their first and validity, the way that we had in the CRISPR 1.0 context.”
The use of CRISPR-Cas9 in eukaryotic cells has been enmeshed in a nearly decade-long bitter battle royale over who invented the genome editing technology. The Patent Trial and Appeal Board (PTAB) last year decided a second patent interference process in favor of the Broad, MIT, and Harvard over the University of California (UC), the University of Vienna, and Nobel laureate Emmanuelle Charpentier, PhD. The first interference was decided in favor of the Broad, MIT, and Harvard in 2018.
“In the case of CRISPR 1.0, in some conceptual sense either the UC’s patents are valid and the Broad Institute’s are not, or vice versa. That’s just not necessarily true here between Harvard with prime editing and MIT with PASTE,” Sherkow said. “One could be valid, one could be not. One could be infringed, one could be not.
“It’s going to come down to whether a company that wants to develop a product in this area is going to be counseled to take a license to one or the other, or both. I think that’s going to be a function of what they think the best fit for their technology is,” Sherkow added.
As a result, he believes researchers will be inclined to use prime editing or PASTE—and thus pursue licenses for one or the other—based on the diseases they are working to treat.
Researchers in some therapeutic areas will be drawn to prime editing if they’re focused on gene correction—such as spinal muscular atrophy, most forms of which are caused by mutations of the survival motor neuron 1 gene.
“Unlike the CRISPR 1.0 situation, where who are we going to take a license to turns on, who do we think is going to win the patent fight, taking a license for prime [editing] or PASTE turns on what is our actual technology, which to be blunt is how we want the licensing system to work,” Sherkow said.
“We don’t want the licensing system to work where people are placing horse bets on winners, with some winners [betting] 90 cents to a dollar and coming in at $1.50, while others are just losing their shirts.”
The post PASTE, Don’t Cut: Genome Editing Tool Looks Beyond CRISPR and Prime appeared first on GEN - Genetic Engineering and Biotechnology News.
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Government
Survey Shows Declining Concerns Among Americans About COVID-19
Survey Shows Declining Concerns Among Americans About COVID-19
A new survey reveals that only 20% of Americans view covid-19 as "a major threat"…
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A new survey reveals that only 20% of Americans view covid-19 as "a major threat" to the health of the US population - a sharp decline from a high of 67% in July 2020.
What's more, the Pew Research Center survey conducted from Feb. 7 to Feb. 11 showed that just 10% of Americans are concerned that they will catch the disease and require hospitalization.
"This data represents a low ebb of public concern about the virus that reached its height in the summer and fall of 2020, when as many as two-thirds of Americans viewed COVID-19 as a major threat to public health," reads the report, which was published March 7.
According to the survey, half of the participants understand the significance of researchers and healthcare providers in understanding and treating long COVID - however 27% of participants consider this issue less important, while 22% of Americans are unaware of long COVID.
What's more, while Democrats were far more worried than Republicans in the past, that gap has narrowed significantly.
"In the pandemic’s first year, Democrats were routinely about 40 points more likely than Republicans to view the coronavirus as a major threat to the health of the U.S. population. This gap has waned as overall levels of concern have fallen," reads the report.
More via the Epoch Times;
The survey found that three in ten Democrats under 50 have received an updated COVID-19 vaccine, compared with 66 percent of Democrats ages 65 and older.
Moreover, 66 percent of Democrats ages 65 and older have received the updated COVID-19 vaccine, while only 24 percent of Republicans ages 65 and older have done so.
“This 42-point partisan gap is much wider now than at other points since the start of the outbreak. For instance, in August 2021, 93 percent of older Democrats and 78 percent of older Republicans said they had received all the shots needed to be fully vaccinated (a 15-point gap),” it noted.
COVID-19 No Longer an Emergency
The U.S. Centers for Disease Control and Prevention (CDC) recently issued its updated recommendations for the virus, which no longer require people to stay home for five days after testing positive for COVID-19.
The updated guidance recommends that people who contracted a respiratory virus stay home, and they can resume normal activities when their symptoms improve overall and their fever subsides for 24 hours without medication.
“We still must use the commonsense solutions we know work to protect ourselves and others from serious illness from respiratory viruses, this includes vaccination, treatment, and staying home when we get sick,” CDC director Dr. Mandy Cohen said in a statement.
The CDC said that while the virus remains a threat, it is now less likely to cause severe illness because of widespread immunity and improved tools to prevent and treat the disease.
“Importantly, states and countries that have already adjusted recommended isolation times have not seen increased hospitalizations or deaths related to COVID-19,” it stated.
The federal government suspended its free at-home COVID-19 test program on March 8, according to a website set up by the government, following a decrease in COVID-19-related hospitalizations.
According to the CDC, hospitalization rates for COVID-19 and influenza diseases remain “elevated” but are decreasing in some parts of the United States.
Spread & Containment
‘I couldn’t stand the pain’: the Turkish holiday resort that’s become an emergency dental centre for Britons who can’t get treated at home
The crisis in NHS dentistry is driving increasing numbers abroad for treatment. Here are some of their stories.
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It’s a hot summer day in the Turkish city of Antalya, a Mediterranean resort with golden beaches, deep blue sea and vibrant nightlife. The pool area of the all-inclusive resort is crammed with British people on sun loungers – but they aren’t here for a holiday. This hotel is linked to a dental clinic that organises treatment packages, and most of these guests are here to see a dentist.
From Norwich, two women talk about gums and injections. A man from Wales holds a tissue close to his mouth and spits blood – he has just had two molars extracted.
The dental clinic organises everything for these dental “tourists” throughout their treatment, which typically lasts from three to 15 days. The stories I hear of what has caused them to travel to Turkey are strikingly similar: all have struggled to secure dental treatment at home on the NHS.
“The hotel is nice and some days I go to the beach,” says Susan*, a hairdresser in her mid-30s from Norwich. “But really, we aren’t tourists like in a proper holiday. We come here because we have no choice. I couldn’t stand the pain.”
This is Susan’s second visit to Antalya. She explains that her ordeal started two years earlier:
I went to an NHS dentist who told me I had gum disease … She did some cleaning to my teeth and gums but it got worse. When I ate, my teeth were moving … the gums were bleeding and it was very painful. I called to say I was in pain but the clinic was not accepting NHS patients any more.
The only option the dentist offered Susan was to register as a private patient:
I asked how much. They said £50 for x-rays and then if the gum disease got worse, £300 or so for extraction. Four of them were moving – imagine: £1,200 for losing your teeth! Without teeth I’d lose my clients, but I didn’t have the money. I’m a single mum. I called my mum and cried.
Susan’s mother told her about a friend of hers who had been to Turkey for treatment, then together they found a suitable clinic:
The prices are so much cheaper! Tooth extraction, x-rays, consultations – it all comes included. The flight and hotel for seven days cost the same as losing four teeth in Norwich … I had my lower teeth removed here six months ago, now I’ve got implants … £2,800 for everything – hotel, transfer, treatments. I only paid the flights separately.
In the UK, roughly half the adult population suffers from periodontitis – inflammation of the gums caused by plaque bacteria that can lead to irreversible loss of gums, teeth, and bone. Regular reviews by a dentist or hygienist are required to manage this condition. But nine out of ten dental practices cannot offer NHS appointments to new adult patients, while eight in ten are not accepting new child patients.
Some UK dentists argue that Britons who travel abroad for treatment do so mainly for cosmetic procedures. They warn that dental tourism is dangerous, and that if their treatment goes wrong, dentists in the UK will be unable to help because they don’t want to be responsible for further damage. Susan shrugs this off:
Dentists in England say: ‘If you go to Turkey, we won’t touch you [afterwards].’ But I don’t worry because there are no appointments at home anyway. They couldn’t help in the first place, and this is why we are in Turkey.
‘How can we pay all this money?’
As a social anthropologist, I travelled to Turkey a number of times in 2023 to investigate the crisis of NHS dentistry, and the journeys abroad that UK patients are increasingly making as a result. I have relatives in Istanbul and have been researching migration and trading patterns in Turkey’s largest city since 2016.
In August 2023, I visited the resort in Antalya, nearly 400 miles south of Istanbul. As well as Susan, I met a group from a village in Wales who said there was no provision of NHS dentistry back home. They had organised a two-week trip to Turkey: the 12-strong group included a middle-aged couple with two sons in their early 20s, and two couples who were pensioners. By going together, Anya tells me, they could support each other through their different treatments:
I’ve had many cavities since I was little … Before, you could see a dentist regularly – you didn’t even think about it. If you had pain or wanted a regular visit, you phoned and you went … That was in the 1990s, when I went to the dentist maybe every year.
Anya says that once she had children, her family and work commitments meant she had no time to go to the dentist. Then, years later, she started having serious toothache:
Every time I chewed something, it hurt. I ate soups and soft food, and I also lost weight … Even drinking was painful – tea: pain, cold water: pain. I was taking paracetamol all the time! I went to the dentist to fix all this, but there were no appointments.
Anya was told she would have to wait months, or find a dentist elsewhere:
A private clinic gave me a list of things I needed done. Oh my God, almost £6,000. My husband went too – same story. How can we pay all this money? So we decided to come to Turkey. Some people we know had been here, and others in the village wanted to come too. We’ve brought our sons too – they also need to be checked and fixed. Our whole family could be fixed for less than £6,000.
By the time they travelled, Anya’s dental problems had turned into a dental emergency. She says she could not live with the pain anymore, and was relying on paracetamol.
In 2023, about 6 million adults in the UK experienced protracted pain (lasting more than two weeks) caused by toothache. Unintentional paracetamol overdose due to dental pain is a significant cause of admissions to acute medical units. If left untreated, tooth infections can spread to other parts of the body and cause life-threatening complications – and on rare occasions, death.
In February 2024, police were called to manage hundreds of people queuing outside a newly opened dental clinic in Bristol, all hoping to be registered or seen by an NHS dentist. One in ten Britons have admitted to performing “DIY dentistry”, of which 20% did so because they could not find a timely appointment. This includes people pulling out their teeth with pliers and using superglue to repair their teeth.
In the 1990s, dentistry was almost entirely provided through NHS services, with only around 500 solely private dentists registered. Today, NHS dentist numbers in England are at their lowest level in a decade, with 23,577 dentists registered to perform NHS work in 2022-23, down 695 on the previous year. Furthermore, the precise division of NHS and private work that each dentist provides is not measured.
The COVID pandemic created longer waiting lists for NHS treatment in an already stretched public service. In Bridlington, Yorkshire, people are now reportedly having to wait eight-to-nine years to get an NHS dental appointment with the only remaining NHS dentist in the town.
In his book Patients of the State (2012), Argentine sociologist Javier Auyero describes the “indignities of waiting”. It is the poor who are mostly forced to wait, he writes. Queues for state benefits and public services constitute a tangible form of power over the marginalised. There is an ethnic dimension to this story, too. Data suggests that in the UK, patients less likely to be effective in booking an NHS dental appointment are non-white ethnic groups and Gypsy or Irish travellers, and that it is particularly challenging for refugees and asylum-seekers to access dental care.
This article is part of Conversation Insights
The Insights team generates long-form journalism derived from interdisciplinary research. The team is working with academics from different backgrounds who have been engaged in projects aimed at tackling societal and scientific challenges.
In 2022, I experienced my own dental emergency. An infected tooth was causing me debilitating pain, and needed root canal treatment. I was advised this would cost £71 on the NHS, plus £307 for a follow-up crown – but that I would have to wait months for an appointment. The pain became excruciating – I could not sleep, let alone wait for months. In the same clinic, privately, I was quoted £1,300 for the treatment (more than half my monthly income at the time), or £295 for a tooth extraction.
I did not want to lose my tooth because of lack of money. So I bought a flight to Istanbul immediately for the price of the extraction in the UK, and my tooth was treated with root canal therapy by a private dentist there for £80. Including the costs of travelling, the total was a third of what I was quoted to be treated privately in the UK. Two years on, my treated tooth hasn’t given me any more problems.
A better quality of life
Not everyone is in Antalya for emergency procedures. The pensioners from Wales had contacted numerous clinics they found on the internet, comparing prices, treatments and hotel packages at least a year in advance, in a carefully planned trip to get dental implants – artificial replacements for tooth roots that help support dentures, crowns and bridges.
In Turkey, all the dentists I speak to (most of whom cater mainly for foreigners, including UK nationals) consider implants not a cosmetic or luxurious treatment, but a development in dentistry that gives patients who are able to have the procedure a much better quality of life. This procedure is not available on the NHS for most of the UK population, and the patients I meet in Turkey could not afford implants in private clinics back home.
Paul is in Antalya to replace his dentures, which have become uncomfortable and irritating to his gums, with implants. He says he couldn’t find an appointment to see an NHS dentist. His wife Sonia went through a similar procedure the year before and is very satisfied with the results, telling me: “Why have dentures that you need to put in a glass overnight, in the old style? If you can have implants, I say, you’re better off having them.”
Most of the dental tourists I meet in Antalya are white British: this city, known as the Turkish Riviera, has developed an entire economy catering to English-speaking tourists. In 2023, more than 1.3 million people visited the city from the UK, up almost 15% on the previous year.
Read more: NHS dentistry is in crisis – are overseas dentists the answer?
In contrast, the Britons I meet in Istanbul are predominantly from a non-white ethnic background. Omar, a pensioner of Pakistani origin in his early 70s, has come here after waiting “half a year” for an NHS appointment to fix the dental bridge that is causing him pain. Omar’s son had been previously for a hair transplant, and was offered a free dental checkup by the same clinic, so he suggested it to his father. Having worked as a driver for a manufacturing company for two decades in Birmingham, Omar says he feels disappointed to have contributed to the British economy for so long, only to be “let down” by the NHS:
At home, I must wait and wait and wait to get a bridge – and then I had many problems with it. I couldn’t eat because the bridge was uncomfortable and I was in pain, but there were no appointments on the NHS. I asked a private dentist and they recommended implants, but they are far too expensive [in the UK]. I started losing weight, which is not a bad thing at the beginning, but then I was worrying because I couldn’t chew and eat well and was losing more weight … Here in Istanbul, I got dental implants – US$500 each, problem solved! In England, each implant is maybe £2,000 or £3,000.
In the waiting area of another clinic in Istanbul, I meet Mariam, a British woman of Iraqi background in her late 40s, who is making her second visit to the dentist here. Initially, she needed root canal therapy after experiencing severe pain for weeks. Having been quoted £1,200 in a private clinic in outer London, Mariam decided to fly to Istanbul instead, where she was quoted £150 by a dentist she knew through her large family. Even considering the cost of the flight, Mariam says the decision was obvious:
Dentists in England are so expensive and NHS appointments so difficult to find. It’s awful there, isn’t it? Dentists there blamed me for my rotten teeth. They say it’s my fault: I don’t clean or I ate sugar, or this or that. I grew up in a village in Iraq and didn’t go to the dentist – we were very poor. Then we left because of war, so we didn’t go to a dentist … When I arrived in London more than 20 years ago, I didn’t speak English, so I still didn’t go to the dentist … I think when you move from one place to another, you don’t go to the dentist unless you are in real, real pain.
In Istanbul, Mariam has opted not only for the urgent root canal treatment but also a longer and more complex treatment suggested by her consultant, who she says is a renowned doctor from Syria. This will include several extractions and implants of back and front teeth, and when I ask what she thinks of achieving a “Hollywood smile”, Mariam says:
Who doesn’t want a nice smile? I didn’t come here to be a model. I came because I was in pain, but I know this doctor is the best for implants, and my front teeth were rotten anyway.
Dentists in the UK warn about the risks of “overtreatment” abroad, but Mariam appears confident that this is her opportunity to solve all her oral health problems. Two of her sisters have already been through a similar treatment, so they all trust this doctor.
The UK’s ‘dental deserts’
To get a fuller understanding of the NHS dental crisis, I’ve also conducted 20 interviews in the UK with people who have travelled or were considering travelling abroad for dental treatment.
Joan, a 50-year-old woman from Exeter, tells me she considered going to Turkey and could have afforded it, but that her back and knee problems meant she could not brave the trip. She has lost all her lower front teeth due to gum disease and, when I meet her, has been waiting 13 months for an NHS dental appointment. Joan tells me she is living in “shame”, unable to smile.
In the UK, areas with extremely limited provision of NHS dental services – known as as “dental deserts” – include densely populated urban areas such as Portsmouth and Greater Manchester, as well as many rural and coastal areas.
In Felixstowe, the last dentist taking NHS patients went private in 2023, despite the efforts of the activist group Toothless in Suffolk to secure better access to NHS dentists in the area. It’s a similar story in Ripon, Yorkshire, and in Dumfries & Galloway, Scotland, where nearly 25,000 patients have been de-registered from NHS dentists since 2021.
Data shows that 2 million adults must travel at least 40 miles within the UK to access dental care. Branding travel for dental care as “tourism” carries the risk of disguising the elements of duress under which patients move to restore their oral health – nationally and internationally. It also hides the immobility of those who cannot undertake such journeys.
The 90-year-old woman in Dumfries & Galloway who now faces travelling for hours by bus to see an NHS dentist can hardly be considered “tourism” – nor the Ukrainian war refugees who travelled back from West Sussex and Norwich to Ukraine, rather than face the long wait to see an NHS dentist.
Many people I have spoken to cannot afford the cost of transport to attend dental appointments two hours away – or they have care responsibilities that make it impossible. Instead, they are forced to wait in pain, in the hope of one day securing an appointment closer to home.
‘Your crisis is our business’
The indignities of waiting in the UK are having a big impact on the lives of some local and foreign dentists in Turkey. Some neighbourhoods are rapidly changing as dental and other health clinics, usually in luxurious multi-storey glass buildings, mushroom. In the office of one large Istanbul medical complex with sections for hair transplants and dentistry (plus one linked to a hospital for more extensive cosmetic surgery), its Turkish owner and main investor tells me:
Your crisis is our business, but this is a bazaar. There are good clinics and bad clinics, and unfortunately sometimes foreign patients do not know which one to choose. But for us, the business is very good.
This clinic only caters to foreign patients. The owner, an architect by profession who also developed medical clinics in Brazil, describes how COVID had a major impact on his business:
When in Europe you had COVID lockdowns, Turkey allowed foreigners to come. Many people came for ‘medical tourism’ – we had many patients for cosmetic surgery and hair transplants. And that was when the dental business started, because our patients couldn’t see a dentist in Germany or England. Then more and more patients started to come for dental treatments, especially from the UK and Ireland. For them, it’s very, very cheap here.
The reasons include the value of the Turkish lira relative to the British pound, the low cost of labour, the increasing competition among Turkish clinics, and the sheer motivation of dentists here. While most dentists catering to foreign patients are from Turkey, others have arrived seeking refuge from war and violence in Syria, Iraq, Afghanistan, Iran and beyond. They work diligently to rebuild their lives, careers and lost wealth.
Regardless of their origin, all dentists in Turkey must be registered and certified. Hamed, a Syrian dentist and co-owner of a new clinic in Istanbul catering to European and North American patients, tells me:
I know that you say ‘Syrian’ and people think ‘migrant’, ‘refugee’, and maybe think ‘how can this dentist be good?’ – but Syria, before the war, had very good doctors and dentists. Many of us came to Turkey and now I have a Turkish passport. I had to pass the exams to practise dentistry here – I study hard. The exams are in Turkish and they are difficult, so you cannot say that Syrian doctors are stupid.
Hamed talks excitedly about the latest technology that is coming to his profession: “There are always new materials and techniques, and we cannot stop learning.” He is about to travel to Paris to an international conference:
I can say my techniques are very advanced … I bet I put more implants and do more bone grafting and surgeries every week than any dentist you know in England. A good dentist is about practice and hand skills and experience. I work hard, very hard, because more and more patients are arriving to my clinic, because in England they don’t find dentists.
While there is no official data about the number of people travelling from the UK to Turkey for dental treatment, investors and dentists I speak to consider that numbers are rocketing. From all over the world, Turkey received 1.2 million visitors for “medical tourism” in 2022, an increase of 308% on the previous year. Of these, about 250,000 patients went for dentistry. One of the most renowned dental clinics in Istanbul had only 15 British patients in 2019, but that number increased to 2,200 in 2023 and is expected to reach 5,500 in 2024.
Like all forms of medical care, dental treatments carry risks. Most clinics in Turkey offer a ten-year guarantee for treatments and a printed clinical history of procedures carried out, so patients can show this to their local dentists and continue their regular annual care in the UK. Dental treatments, checkups and maintaining a good oral health is a life-time process, not a one-off event.
Many UK patients, however, are caught between a rock and a hard place – criticised for going abroad, yet unable to get affordable dental care in the UK before and after their return. The British Dental Association has called for more action to inform these patients about the risks of getting treated overseas – and has warned UK dentists about the legal implications of treating these patients on their return. But this does not address the difficulties faced by British patients who are being forced to go abroad in search of affordable, often urgent dental care.
A global emergency
The World Health Organization states that the explosion of oral disease around the world is a result of the “negligent attitude” that governments, policymakers and insurance companies have towards including oral healthcare under the umbrella of universal healthcare. It as if the health of our teeth and mouth is optional; somehow less important than treatment to the rest of our body. Yet complications from untreated tooth decay can lead to hospitalisation.
The main causes of oral health diseases are untreated tooth decay, severe gum disease, toothlessness, and cancers of the lip and oral cavity. Cases grew during the pandemic, when little or no attention was paid to oral health. Meanwhile, the global cosmetic dentistry market is predicted to continue growing at an annual rate of 13% for the rest of this decade, confirming the strong relationship between socioeconomic status and access to oral healthcare.
In the UK since 2018, there have been more than 218,000 admissions to hospital for rotting teeth, of which more than 100,000 were children. Some 40% of children in the UK have not seen a dentist in the past 12 months. The role of dentists in prevention of tooth decay and its complications, and in the early detection of mouth cancer, is vital. While there is a 90% survival rate for mouth cancer if spotted early, the lack of access to dental appointments is causing cases to go undetected.
The reasons for the crisis in NHS dentistry are complex, but include: the real-term cuts in funding to NHS dentistry; the challenges of recruitment and retention of dentists in rural and coastal areas; pay inequalities facing dental nurses, most of them women, who are being badly hit by the cost of living crisis; and, in England, the 2006 Dental Contract that does not remunerate dentists in a way that encourages them to continue seeing NHS patients.
The UK is suffering a mass exodus of the public dentistry workforce, with workers leaving the profession entirely or shifting to the private sector, where payments and life-work balance are better, bureaucracy is reduced, and prospects for career development look much better. A survey of general dental practitioners found that around half have reduced their NHS work since the pandemic – with 43% saying they were likely to go fully private, and 42% considering a career change or taking early retirement.
Reversing the UK’s dental crisis requires more commitment to substantial reform and funding than the “recovery plan” announced by Victoria Atkins, the secretary of state for health and social care, on February 7.
The stories I have gathered show that people travelling abroad for dental treatment don’t see themselves as “tourists” or vanity-driven consumers of the “Hollywood smile”. Rather, they have been forced by the crisis in NHS dentistry to seek out a service 1,500 miles away in Turkey that should be a basic, affordable right for all, on their own doorstep.
*Names in this article have been changed to protect the anonymity of the interviewees.
For you: more from our Insights series:
GP crisis: how did things go so wrong, and what needs to change?
Insomnia: how chronic sleep problems can lead to a spiralling decline in mental health
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Diana Ibanez Tirado receives funding from the School of Global Studies, University of Sussex.
pound pandemic treatment therapy spread recovery iran brazil european europe uk germany ukraine world health organizationSpread & Containment
The Coming Of The Police State In America
The Coming Of The Police State In America
Authored by Jeffrey Tucker via The Epoch Times,
The National Guard and the State Police are now…
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Authored by Jeffrey Tucker via The Epoch Times,
The National Guard and the State Police are now patrolling the New York City subway system in an attempt to do something about the explosion of crime. As part of this, there are bag checks and new surveillance of all passengers. No legislation, no debate, just an edict from the mayor.
Many citizens who rely on this system for transportation might welcome this. It’s a city of strict gun control, and no one knows for sure if they have the right to defend themselves. Merchants have been harassed and even arrested for trying to stop looting and pillaging in their own shops.
The message has been sent: Only the police can do this job. Whether they do it or not is another matter.
Things on the subway system have gotten crazy. If you know it well, you can manage to travel safely, but visitors to the city who take the wrong train at the wrong time are taking grave risks.
In actual fact, it’s guaranteed that this will only end in confiscating knives and other things that people carry in order to protect themselves while leaving the actual criminals even more free to prey on citizens.
The law-abiding will suffer and the criminals will grow more numerous. It will not end well.
When you step back from the details, what we have is the dawning of a genuine police state in the United States. It only starts in New York City. Where is the Guard going to be deployed next? Anywhere is possible.
If the crime is bad enough, citizens will welcome it. It must have been this way in most times and places that when the police state arrives, the people cheer.
We will all have our own stories of how this came to be. Some might begin with the passage of the Patriot Act and the establishment of the Department of Homeland Security in 2001. Some will focus on gun control and the taking away of citizens’ rights to defend themselves.
My own version of events is closer in time. It began four years ago this month with lockdowns. That’s what shattered the capacity of civil society to function in the United States. Everything that has happened since follows like one domino tumbling after another.
It goes like this:
1) lockdown,
2) loss of moral compass and spreading of loneliness and nihilism,
3) rioting resulting from citizen frustration, 4) police absent because of ideological hectoring,
5) a rise in uncontrolled immigration/refugees,
6) an epidemic of ill health from substance abuse and otherwise,
7) businesses flee the city
8) cities fall into decay, and that results in
9) more surveillance and police state.
The 10th stage is the sacking of liberty and civilization itself.
It doesn’t fall out this way at every point in history, but this seems like a solid outline of what happened in this case. Four years is a very short period of time to see all of this unfold. But it is a fact that New York City was more-or-less civilized only four years ago. No one could have predicted that it would come to this so quickly.
But once the lockdowns happened, all bets were off. Here we had a policy that most directly trampled on all freedoms that we had taken for granted. Schools, businesses, and churches were slammed shut, with various levels of enforcement. The entire workforce was divided between essential and nonessential, and there was widespread confusion about who precisely was in charge of designating and enforcing this.
It felt like martial law at the time, as if all normal civilian law had been displaced by something else. That something had to do with public health, but there was clearly more going on, because suddenly our social media posts were censored and we were being asked to do things that made no sense, such as mask up for a virus that evaded mask protection and walk in only one direction in grocery aisles.
Vast amounts of the white-collar workforce stayed home—and their kids, too—until it became too much to bear. The city became a ghost town. Most U.S. cities were the same.
As the months of disaster rolled on, the captives were let out of their houses for the summer in order to protest racism but no other reason. As a way of excusing this, the same public health authorities said that racism was a virus as bad as COVID-19, so therefore it was permitted.
The protests had turned to riots in many cities, and the police were being defunded and discouraged to do anything about the problem. Citizens watched in horror as downtowns burned and drug-crazed freaks took over whole sections of cities. It was like every standard of decency had been zapped out of an entire swath of the population.
Meanwhile, large checks were arriving in people’s bank accounts, defying every normal economic expectation. How could people not be working and get their bank accounts more flush with cash than ever? There was a new law that didn’t even require that people pay rent. How weird was that? Even student loans didn’t need to be paid.
By the fall, recess from lockdown was over and everyone was told to go home again. But this time they had a job to do: They were supposed to vote. Not at the polling places, because going there would only spread germs, or so the media said. When the voting results finally came in, it was the absentee ballots that swung the election in favor of the opposition party that actually wanted more lockdowns and eventually pushed vaccine mandates on the whole population.
The new party in control took note of the large population movements out of cities and states that they controlled. This would have a large effect on voting patterns in the future. But they had a plan. They would open the borders to millions of people in the guise of caring for refugees. These new warm bodies would become voters in time and certainly count on the census when it came time to reapportion political power.
Meanwhile, the native population had begun to swim in ill health from substance abuse, widespread depression, and demoralization, plus vaccine injury. This increased dependency on the very institutions that had caused the problem in the first place: the medical/scientific establishment.
The rise of crime drove the small businesses out of the city. They had barely survived the lockdowns, but they certainly could not survive the crime epidemic. This undermined the tax base of the city and allowed the criminals to take further control.
The same cities became sanctuaries for the waves of migrants sacking the country, and partisan mayors actually used tax dollars to house these invaders in high-end hotels in the name of having compassion for the stranger. Citizens were pushed out to make way for rampaging migrant hordes, as incredible as this seems.
But with that, of course, crime rose ever further, inciting citizen anger and providing a pretext to bring in the police state in the form of the National Guard, now tasked with cracking down on crime in the transportation system.
What’s the next step? It’s probably already here: mass surveillance and censorship, plus ever-expanding police power. This will be accompanied by further population movements, as those with the means to do so flee the city and even the country and leave it for everyone else to suffer.
As I tell the story, all of this seems inevitable. It is not. It could have been stopped at any point. A wise and prudent political leadership could have admitted the error from the beginning and called on the country to rediscover freedom, decency, and the difference between right and wrong. But ego and pride stopped that from happening, and we are left with the consequences.
The government grows ever bigger and civil society ever less capable of managing itself in large urban centers. Disaster is unfolding in real time, mitigated only by a rising stock market and a financial system that has yet to fall apart completely.
Are we at the middle stages of total collapse, or at the point where the population and people in leadership positions wise up and decide to put an end to the downward slide? It’s hard to know. But this much we do know: There is a growing pocket of resistance out there that is fed up and refuses to sit by and watch this great country be sacked and taken over by everything it was set up to prevent.
The Coming Of The Police State In America
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